Submissions for variant NM_002834.5(PTPN11):c.205G>A (p.Glu69Lys)

dbSNP: rs397507511

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000210038	SCV000265841	likely pathogenic	not provided	2015-09-22	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV001250211	SCV001424481	likely pathogenic	Noonan syndrome 1		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415881	SCV002725115	uncertain significance	Cardiovascular phenotype	2017-03-10	criteria provided, single submitter	clinical testing	The p.E69K variant (also known as c.205G>A), located in coding exon 3 of the PTPN11 gene, results from a G to A substitution at nucleotide position 205. The glutamic acid at codon 69 is replaced by lysine, an amino acid with similar properties. This alteration has been described as an acquired somatic change in multiple cancer types, including: juvenile myelomonocytic leukemia (JMML), acute lymphoblastic leukemia (ALL), neuroblastoma, and astrocytoma (Loh ML et al. Blood, 2004 Mar;103:2325-31; Tartaglia M et al. Blood, 2004 Jul;104:307-13; Bentires-Alj M et al. Cancer Res., 2004 Dec;64:8816-20; Jones DT et al. Nat. Genet., 2013 Aug;45:927-32). In vivo functional studies have shown that this alteration results in increased and phosphatase activity compared to wild-type (Bentires-Alj M et al. Cancer Res., 2004 Dec;64:8816-20; Eminaga S et al. J. Biol. Chem., 2008 May;283:15328-38). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. There have been no reports of individuals clinically affected with Noonan syndrome or related disorders; since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV005251095	SCV005902167	likely pathogenic	Juvenile myelomonocytic leukemia	2024-08-02	criteria provided, single submitter	clinical testing	A PTPN11 c.205G>A (p.Glu69Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant, to our knowledge, has not been reported in the medical literature in individuals with Noonan syndrome. This variant has been reported in the ClinVar database as a likely pathogenic variant by two submitters and a germline variant of uncertain significance by one submitter (ClinVar Variation ID: 224414). The PTPN11 c.205G>A (p.Glu69Lys) variant has been reported in numerous types of cancers in the cancer database COSMIC (Genomic Mutation ID: COSV61004768). It is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. Other variants in the same codon (c.205G>C (p.Glu69Gln), c.206A>T (p.Glu69Val), c.206A>C (p.Glu69Ala) have been reported in individuals affected with Noonan syndrome (Musante L et al., PMID:12634870; Atik Tet al., PMID: 26817465; Pierpont E et al., PMID: 20186801; ClinVar ID: 1997356). This variant resides within a region, the N-SH2 domain, amino acids 1-104, of PTPN11 that is defined as a critical functional domain (Musante L et al., PMID:12634870; Gelb BD et al., PMID: 29493581; Tartaglia M et al., PMID: 11992261; Hof P et al., PMID: 9491886; Zenker M al., PMID: 15001945). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to PTPN11 function. In support of this prediction, functional studies show that this variant promotes interactions between the N-SH2 domain and upstream signaling molecules by inducing a conformational change to an open state, allowing substrate entry into the catalytic site and thereby enhancing ERK signaling (Eminaga S et al., PMID: 18378677; Liu X et al., PMID: 21799948; Bocchinfuso G et al., PMID: 17177198; Fragale A et al., PMID: 14974085). The PTPN11 gene is defined by ClinGen's RASopathy expert panel as a gene with a low rate of benign missense variation and where pathogenic missense variants are a common disease mechanism (Gelb BD et al., PMID: 29493581). Based on available information and an internally developed protocol informed by the ACMG/AMP guidelines for variant interpretation and gene-specific practices from the ClinGen Criteria Specification Registry (Leon-Quintero FZ et al., PMID: 39434542), the PTPN11 c.205G>A (p.Glu69Lys) variant is classified as likely pathogenic.